Mahir Rahman (MR): Hello, everyone, this is Mahir Rahman. Welcome to the Autism Science Foundation Weekly Science Podcast. I’m subbing in for Alycia for an interview I conducted with Dr. Alex Kolevzon of Mount Sinai. Hope you enjoy the story.

MR: A Mount Sinai research team led by Dr. Alex Kolevzon is investigating if a compound known as insulin-like growth factor 1, also known as IGF-1, can be used as a treatment for autism. Dr. Kolevzon is a child psychiatrist and the clinical director of the Seaver Autism Center in the Icahn School of Medicine at Mount Sinai in New York. He received the Autism Science Foundation Treatment Grant in 2013. He sat down with ASF to discuss his current study. We began the interview by discussing the autism-related disorder Phelan-McDermid syndrome, also known as PMS.

Alex Kolevzon (AK): Phelan-McDermid syndrome is a neurodevelopmental disorder that causes autism. It is due to a deletion or mutation of the SHANK3 gene, which is located at the terminal end of chromosome 22. There’s two copies of the SHANK3 gene, we all have two copies of it. And so, in Phelan-McDermid syndrome, you’re basically missing one copy and that’s called haploinsufficiency.

MR: Are you wondering what happens if you miss one copy of the SHANK3 gene? Well, SHANK3 is a gene that codes for a protein that helps brain cells communicate with each other in order to make useful connections during development. When one copy of the SHANK3 gene is missing, certain brain cells cannot communicate with each other, leading to a number of problems.

AK: So based on very large genetic studies, it seems as if Phelan-McDermid syndrome or SHANK3 deletions and mutations account for about 1% of autism, and not everyone with Phelan-McDermid Syndrome has autism, so there’s going to be additional cases beyond that. So really it’s very common. We’re just now starting to routinely diagnose people.

MR: How can some kids with PMS have autism and others not?

AK: Well, autism is a behavioral diagnosis. It’s really just a collection of symptoms, social impairments, language impairments, restricted and repetitive behaviors, and, you know, many different people with autism look very, very different. So some kids have… with Phelan-McDermid syndrome have a lot of social motivations, social interests, social engagements. And despite being significantly cognitively delayed, the social domain is a relative strength for them, and as a result, they don’t really meet the criteria for an autism spectrum disorder. We’re talking about maybe 15% to 20% of them. So the vast majority of people with Phelan-McDermid syndrome do meet the criteria for autism. But it’s important to understand that if you take a given biological cause of a syndrome, the clinical features of that syndrome could be very, very wide.

MR: To reiterate, it’s important to understand that, like autism, the symptoms of PMS can vary. They can vary enough that some children with PMS don’t meet the criteria for an autism diagnosis, but most of the time, they will. That said, the symptoms seen in autism might be based on biology similar to that of PMS.

AK: Within the broader universe of people with autism, and especially people with autism where there isn’t a known cause — what we call idiopathic autism, it seems as those a subset of them appear clinically, and even on some biological measures, look like people with Phelan-McDermid syndrome.

MR: If two conditions have similar biology, the same treatment may be able to help both. The search for a treatment for PMS and idiopathic autism led Dr. Kolevzon’s team to a group of compounds known as growth factors. Growth factors can help cells grow, change, and make new connections, what scientists call plasticity.

AK: A growth factor can promote growth, promote synaptic plasticity, which is what is essentially absent in Phelan-McDermid syndrome. So we started doing this study with a drug called insulin-like growth factor, which we know crosses into the brain, we know it promotes synaptic maturity, synaptic plasticity, nerve cell growth, and we did a couple of small studies, both of which were very, very promising.

MR: In a pilot clinical trial using IGF-1, Dr. Kolevzon’s team found children with PMS tolerated the drug. They also found that the children treated with IGF-1 had reduced expression of two core symptoms of autism – social withdrawal and repetitive behaviors.

AK: We looked at social symptoms and repetitive behavior symptoms because those are core domains of autism. And those are both studied in this trial using a parent-report measure, and we saw improvement in both those domains in the trial with IGF-1.

Dr. Kolevzon’s lab during a team meeting.

MR: Dr. Kolevzon’s team made sure every participant had the opportunity to receive the IGF-1 treatment in the trial by employing a crossover design.

AK: Patients got drugs for 12 weeks, or placebo, and they switched to the other condition, so each patient essentially acted as their own control and treatment was for 12 weeks and placebo was for 12 weeks in random order. We applied the exact same design to the trial in idiopathic autism.

MR: Employing a crossover design was an intentional decision by his team.

AK: One of the biggest obstacles to success in clinical trials is recruitment. One of the biggest obstacles to families wanting to participate is the idea of being on placebo and not getting access to the active treatment. So we purposely designed the trial with everyone getting active treatment.

MR: Based on the findings made by Dr. Kolevzon’s team, IGF-1 appears to be a safe treatment that offers notable improvements in core symptoms of autism, so why is it not considered an effective treatment yet? Dr. Kolevzon hopes to address that question with his current study.

AK: The fear in the field in general is we might be studying an effective medicine but we are not able to show improvement because our measures are not ideal. Either we’re not measuring the right thing, measures aren’t sensitive enough, we’re not able to really account for the placebo effect because they’re so biased. So we’ve been focusing a lot more on more objective, more quantifiable measures, trying to develop new ways of looking at symptoms.

MR: His current study is focusing on sensory reactivity symptoms. Many people with PMS and autism have sensory issues, including varying sensitivity to light and sound and atypical interests in specific textures and temperatures. In order to examine brain activity in general and during periods of sensory reactivity, his lab uses a technique called electroencephalography, or EEG. Dr. Kolevzon’s team will be examining how IGF-1 affects sensory reactivity and brain activity following IGF treatment

AK: That’s really an important symptom, it’s a symptom that’s virtually universal. All kids with Phelan-McDermid syndrome, at least all the kids that we have evaluated, have some sensory reactivity symptoms. Often, they are hyporeactive.

MR: Meaning that these kids often have a decreased response to sensory stimuli. Say a child with sensory hyporeactivity entered a room with very loud speakers. The child might not be bothered by, or let alone react to, the volume. With IGF-1 treatment, Dr. Kolevzon believes his team will be able to observe any change of those sensory reactivity symptoms over the course of the clinical trial.

AK: This is a trial that is pretty burdensome for families because the way that IGF-1 is delivered is through subcutaneous injection. So families are taught to monitor their children’s glucose levels because one of the main side effects can be low blood sugar, and they’re also taught how to inject the children twice a day with small amounts of IGF-1. It’s a very, very small needle and actually, it’s probably the element of the study that people are most concerned about when they first consider it, and it ends up in actually 19 out of 19 cases not to be a really big issue. The children, because they have the sensory hyporeactivity, aren’t especially averse to the shots and the parents become remarkably expert very, very quickly. We give them a big manual with lots of instructions. We show them exactly how big, and in this case, how tiny the needle is, but then, the very first day that they actually get the injection, I give it to them myself.

MR: Dr. Kolevzon and his team understand that they’re asking a lot from the families choosing to participate in the study. They take great strides in order to prepare and help the families throughout the recruitment and trial process.

AK: For me to say things like, “Oh, this is not a big deal,” isn’t helpful. Obviously, this is a big deal, we acknowledge that on the onset, but for me to also encourage them and say, “Look, it’s going to feel scary and then you’re going to be quite good at it.” That’s one thing. I think the other thing is that they don’t feel alone in this, right? They don’t have to make decisions on their own. They don’t have to worry about dosing on their own. You know, if they see anything concerning, they don’t need to decide what to do about that. They have unfettered access to me. We exchange cell phone numbers early on and then, the other thing I say to them is, “You know, if you have any concerns at all, skip the dose. That’s it. You get to control that. If you don’t want to give your child the does for whatever reason, just skip the dose. There will not be any harm in that.” Then, we just take it from there.

MR: For those autism families that are listening, Dr. Kolevzon has a message for you.

AK: “Come participate!” I’d say that if you’re not convinced that a clinical trial is a good idea, that’s okay also. Come just to get to know us. Let us get to know you. And then, you know, we’ll figure it out. Nobody has ever required anybody to participate in a clinical trial. We definitely respect how scary it can be and how hard it can be. So it’s really all about just the fit.

MR: You can learn more about this study on asfpodcast.org. Thanks for listening.

Life is a sensory experience! We touch, hear, feel our muscles, move our bodies, taste, and smell and use vision to take in information from the environment, process and integrate it to act and interact as well as to learn and grow. Upwards of 80% of persons with Autism Spectrum Disorder (ASD) experience differences in the way they perceive and process sensory information. This impacts the ways in which they participate in functional tasks such as speaking, moving, eating, dressing, interacting with others, playing, learning and working. These sensory features are now part of the diagnosis of autism in the DSM5.

As an occupational therapist and a neuroscientist, my interest in the sensory features of ASD developed from working with children and families who often articulated how decreased sensory perception, integration or sensory sensitivities affected their everyday lives. As we worked together to improve independence and skill in daily life activities, success at school and to foster social engagement, it became clear that we needed to address these sensory differences in order to achieve their desired goals. We used the principles of sensory integration (Ayres, 2005; Bundy, et al, 2001) to target these issues and saw positive results! To share our knowledge and test this approach we received funding to write a manualized protocol (Schaaf & Mailloux, 2015), test its effectiveness, and publish our findings (Schaaf, et al, 2014). This study showed that children with ASD who received the occupational therapy using sensory integration treatment performed significantly better in functional skills and individual goals compared to controls.

Courtesy: Roseann Schaaf, PhD

We are now conducting a larger, more comprehensive study and are seeking families who have a child with ASD aged 6-9.5 years who may want to participate in the study. This study is a collaboration with Thomas Jefferson University and Albert Einstein Medical Center and is located in the Bronx, NY. Children will receive a full diagnostic battery and then be randomized to one of the treatments (Sensory Integration or a behavioral intervention) and will receive 3 one-hour sessions/week for a total of 30 treatments. Parents must be willing to travel to Albert Einstein College of Medicine (1225 Morris Park Avenue, Suite 1-C, Bronx, NY 10461). Participants will receive a total of $250 and a report of the child’s performance and assessment data at the end of the study. Children have a 1/3 chance of being randomized into the “No Treatment” arm of the study but will still receive all assessments and stipends for participation.

The report will indicate whether the child performed below, at, or above average in the last round of the following tests:

More and more, researchers and clinicians are thinking about how advances in technology can be leveraged for interventions for children with autism. Tablets, computers, and video games have become increasingly available to children in their daily lives. At the same time, the American Academy of Pediatrics has put forth clear screen time guidelines for children, and many parents worry about their children spending too much time in front of a screen or with devices.

In the autism field, technology is providing promising avenues for early detection and intervention. For example, a recent study describes the use of mobile technology to screen for autism in young children. Others have developed apps and virtual reality systems through which treatments can be delivered. But what good are advances in technology-based interventions if parents aren’t interested in utilizing them?

Researchers at the UC Davis MIND Institute on the UC Davis Medical Center campus in Sacramento are conducting a study of parental perceptions of use of technology in treatment of impulsivity in 4 to 7-year-olds with autism spectrum disorder. Parents of 4 to 7-year-old children who have been diagnosed with autism spectrum disorder (ASD) can participate. Families can expect to complete of several online questionnaires about: Your family, your opinions about technology in treatment, and your child’s behavior. These questionnaires will take about 10 minutes of your time.

Sleep is an essential component of a healthy life, like food and oxygen. When we don’t sleep well, we feel irritable and have difficulty concentrating. With this in mind, imagine how a child on the autism spectrum feels and behaves without sleep (and how their sleep-deprived caregivers feel)!

Given how common sleep problems are, and how profoundly they affect children and their families, it is timely to consider what we already know and what the future holds in our understanding of sleep in autism spectrum disorders (ASD).

What we’ve learned so far: Sleep problems are common in children with ASD, have many causes, and affect child and family functioning.

Sleep problems are common in children with autism spectrum disorders (ASD) — ranging from 50-80% (Couturier et al., 2005; Krakowiak et al., 2008; Souders et al., 2009; Goldman et al. 2011), with similar rates across all ages and cognitive levels. Insomnia, defined as difficulty falling asleep or staying asleep, is the most common sleep problem. Causes (Reynolds and Malow, 2011) range from medical conditions (e.g., gastrointestinal disorders, seizures, sleep apnea, attention deficit disorder, anxiety) and the medications used to treat these conditions (e.g., stimulants, antidepressants) to behavioral factors unique to the child with autism (for example, sensory sensitivities, difficulty transitioning to bedtime activities). Children, regardless of language abilities, may not understand parents expectations about sleep. Parents, in turn, may be too overwhelmed by other priorities and stressors to put a sleep plan in place. Proper identification of the causes of sleep difficulties in children with ASD is critical to successful treatment.

Behavioral and pharmacological treatments that improve sleep positively affect daytime functioning in the child and family (as reviewed in Malow et al., 2012) and may minimize the need for medications that target behavioral symptoms. For example, in 80 children receiving sleep education delivered by their parents (Malow et al., 2013), improvements in anxiety, attention, repetitive behavior, pediatric quality of life, and parenting sense of competence were also observed. While improving sleep does not necessarily change the core features of ASD, addressing sleep concerns may ameliorate co-occurring medical conditions such as epilepsy or anxiety. A well-rested child may also be more engaged in therapies that improve social interactions, and his well-rested parents may be empowered to advocate more effectively for his needs.

What we need to learn: What therapies for sleep are effective? Can we predict which treatments will work for subgroups of children?

We still have much more to learn about which therapies are effective for sleep in children with ASD. In particular, we need to understand the impact of treating co-occurring medical and psychiatric conditions (e.g., gastrointestinal disorders, anxiety) on sleep-onset and sleep-maintenance insomnia. For example, insomnia, anxiety, and GI disturbances may coexist in the same child, but whether one causes or contributes to the other coexisting conditions is unresolved. An alternative possibility is that insomnia, anxiety, and GI disturbance share an underlying mechanism. One possible mechanism may be autonomic dysfunction (Kushki, 2013), with sympathetic hyperarousal and parasympathetic underarousal.

While behavioral treatments for sleep have shown promise in ASD and other neurodevelopmental disorders (Malow et al., 2013; Weiskop et al., 2005 and others reviewed in Vriend, 2011), determining subgroups of children who are most responsive to these therapies are needed. For example, children with short sleep duration and frequent night wakings (in whom medical causes of sleep disturbance have been excluded), or those with limited verbal skills, may have a differing treatment response to behavioral interventions than children with sleep onset delay. This differing response may result from biological causes, or alternatively, a poorer response to theintervention. In those requiring medications, we need to determine which medicines are safe and effective for a variety of sleep problems (sleep onset delay, night wakings). Supplemental melatonin has been studied to a greater extent than any other medication for sleep in ASD, but large well-controlled studies have been limited (Rossignol, 2011). Genetic factors, including those related to melatonin synthesis, may also be important (Melke, 2008) in determining which child may respond to a specific therapy.

Another subgroup of individuals with ASDs worthy of study are adolescents and young adults. My colleagues at Vanderbilt are studying sleep patterns this population at baseline (Dr. Suzanne Goldman, funding from Autism Speaks), and with behavioral treatment (Dr. Whitney Loring, funding from Organization for Autism Research).

The area of sleep and autism is ripe for continued research, in terms of causes, treatments, and overlap with many other areas, ranging from medical co-occurring conditions to genetic and other biological markers to treatment trials. Being vigilant (pun intended) to the role of sleep in autism research has high potential to advance our knowledge of autism subtypes as well as our toolbox for real world treatments that impact people with ASD and their families.

(March 29, 2012—New York) The Centers for Disease Control in Atlanta today reported that 1 in 88 children were diagnosed with an autism spectrum disorder (ASD) in 2008. That’s a 23% increase from 2006 when the prevalence rate was 1 in 110. Autism spectrum disorders are almost five times more common among boys than girls – with 1 in 54 boys identified.

“One thing the data tells us with certainty – there are many children and families who need help,” CDC Director Thomas Frieden, M.D., M.P.H said in a press release. “We must continue to track autism spectrum disorders because this is the information communities need to guide improvements in services to help children.” On a noontime call with media and advocates, Dr. Frieden added “Doctors are getting better at diagnosing autism. It’s possible that the increase is entirely the result of better detection.”

The identified prevalence of ASDs in U.S. children aged 8 years was estimated through a retrospective review of records in multiple sites participating in the CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network. Data were collected from existing records in 14 ADDM Network sites (Alabama, Arizona, Arkansas, Colorado, Florida, Georgia, Maryland, Missouri, New Jersey, North Carolina, Pennsylvania, South Carolina, Utah and Wisconsin)for 2008. Children aged 8 years met the case definition for an ASD if their records documented behaviors consistent with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria for autistic disorder, pervasive developmental disorder–not otherwise specified (PDD NOS), or Asperger disorder. Presence of an identified ASD was determined through a review of data abstracted from developmental evaluation records by trained clinician reviewers.

“These are not just numbers, these are real people with real needs” said Alison Singer, president of the Autism Science Foundation. “These are families that are exploding. We have to focus on building the infrastructure to provide education and services to all of these people and their families. And we have to focus on what is fueling the increase in prevalence, and that means investing in research. We have learned so much about autism’s genetic underpinnings in the last few years. We have to understand more about what’s going wrong in the brain that causes autism so that we can develop appropriate medical treatments.”

“We need to accelerate research into causes” said Dr. Coleen Boyle, Director of the CDC’s Center for Birth Defects and Developmental Disabilities. “Tracking helps identify potential risk factors. Because of tracking we now know more about how advanced parental age and premature birth confer increased risk for autism.”

Autism spectrum disorders (ASDs) are a group of developmental disabilities characterized by atypical development in socialization, communication, and behavior. ASDs typically are apparent before age 3 years and sometimes can be diagnosed as early as 14 months, with associated impairments affecting multiple areas of a person’s life. Because no biologic marker exists for ASDs, identification is made by professionals who evaluate a child’s developmental progress to identify the presence of developmental disorders.

This is a guest post from ASF Science Writer Jerri Sparks Kaiser. Jerri, a parent of four children, one of whom has autism, blogs for ASF from a parent’s perspective about the latest autism research. A former Congressional Press Secretary, Jerri is an experienced science writer and has written specifically about autism for many years. Before her life in PR, she was a trained researcher having earned her B.A. in Psychology at UCLA. She currently lives with her family in New York.

By Jerri Sparks Kaiser

Photo: jshj

A new study by researchers at Vanderbilt University about giving melatonin to autistic children to help them sleep was published a few weeks ago and it deserves some attention. Researchers gave 1 mg to 3 mg of melatonin to children with autism ages 3-9 years and noted improved sleep onset. They are now trying to conduct larger scale studies.

Sleep difficulties have always been a problem for my son Jared. One of the first things I noticed about his development was that he didn’t sleep very many hours in a row. In fact, for the first 4 years he only slept 4 ½ hours at a time and after that it was still just 6 hours. I don’t recall when he finally began sleeping at least 8 hours at a stretch (perhaps it was around age 7) but I know that it didn’t happen without medications prescribed by doctors. Sleep deprivation was making it difficult for me and my spouse to conduct our daily lives and we resorted to sleeping in shifts. It is estimated that 50-80% of those with ASD are affected by insomnia and that impacts families as well.

I remember sleepily waiting in the elevator at UCLA Medical Center to take Jared to an early pediatrician appointment. He must have been around 10 weeks old. Beside me in the elevator was another couple with a young infant like my son and we exchanged pleasantries about each baby’s cuteness and then I asked them how they were coping with the lack of sleep. They smiled at each other and said “She’s already sleeping six hours in a row…” It was the first of many moments where I sought solace in parents going through the same thing I was going through only to have that hope – that need – dashed.[

Since that time my son has gradually learned to sleep a lot longer, but his sleep is still shallow at times. The slightest noise can wake him and then he’s up for the day no matter how little sleep he had before he was awakened. When he is particularly excited about something that’s happening the next day he can’t sleep and will stay awake for 24 hours or more until the anticipated event has occurred. We are searching for something to help him with this latest symptom, not only for his own health but also for the sake of our family. Sleep disturbance affects everyone, not just the person experiencing it. I never thought I’d still be going through sleep deprivation 14 years later.

We did try melatonin for Jared when he was much younger. I remember it working but as fate would have it, other symptoms, such as running away and behavioral outbursts, took precedence over his sleep supplement and so we had to remove melatonin from his treatment. The new medications he was placed on took care of his sleep issue until just recently. This new study makes me wonder if perhaps we could introduce melatonin into his treatment once again and I am going to call his doctor about this.

Recently Jared asked me why he couldn’t sleep. This is an emerging behavior because Jared is just now beginning to let us into his inner thoughts. It’s very exciting! The fact that he’s wondering about his own behaviors is encouraging to me. I didn’t know what to tell him so I said the only thing a mother can say when she doesn’t have the answer yet: “I don’t know honey, but I’m going to find out and make it all better.” And I will, someday, somehow.

How can early intervention affect brain structure?
Why do some children “recover” from autism while others continue to struggle after EI?

Dr. Eric Courchesne, keynote speaker at IMFAR, describes the underlying brain biology of autism and shares new findings showing differences in brain structure in people with autism. These changes originate in the second trimester of prenatal life when there is a tremendous overproduction of brain cells in individuals with autism that create patches of functional abnormality. Dr. Courchesne describes how early intervention alters brain connections and structure, and discusses the “recovery genetics” of autism, including new understanding about why some kids recover from autism while other children continue to struggle.